Cytochrome P450s in Drug Metabolism and Disease

UNM Department of Biochemistry & Molecular Biology
Developed and administered by the Division of Biocomputing
Fall 2005

Slides and downloads (requires password)

Objectives: Lecture 1

  • Case Study: CYP3A4 substrates & inhibitors DDI
  • Learn the difference between oxidase/oxygenase reaction
  • Metabolism of xenobiotics via P450s – overview
  • Introduce fundamentals of monooxygenase reaction (substrate, O2, NAD(P)H, H+) and learn the catalytic cycle of P450s
  • Learn the structure of the P450 heme moiety
  • Introduce low/high spin transition and explain how this activates the enzyme upon water elimination from the heme
  • Dioxygen species activation in P450s (homolysis vs heterolysis)
  • Learn examples of reactions catalyzed by P450s
  • Introduce class I and class II P450s and structural examples

Objectives: Lecture 2

  • Recap metabolism of xenobiotics, catalytic cycle and role of water in the lowspin / high-spin transition
  • Introduce the dioxygen activation across other enzyme systems (follow-up from lecture 1)
  • The uncoupling reaction, the internal solvent channel (proton transfer) and the aqueduct (water exiting catalytic site)
  • The cysteine heme-iron ligand signature as fundamental feature of ALL P450 primary sequences
  • Suggested mechanism for P420 formation
  • What is the difference between type I and type II inhibitors (e.g., water displacement).
  • P450s in drug metabolism
  • Overview: which CYP does what
  • Vitamin D3 endocrine system – role of P450s
  • Case Study: Amiodarone

Objectives: Lecture 3

  • Recap P450sin drug metabolism
  • Recap: VitaminD3 endocrine system –role of P450s
  • Introduce Family 1 (1A1, 1A2) & list of drugs metabolized by CYP1A2.
  • Introduce Family 2 –2C, 2D6 and 2E1
  • Introduce Family 3 –3A4
  • Note: Crystalstructure studies of2C9 & 3A4are
  • Case Study: Tamoxifen vs. Paroxetine

Objectives: Lecture 4

  • Re-emphasize DDI and their importance in disease
  • Focused on the importance of DDIs in drugs with low bioavailability, of drugs that can cause lethal interactions (Terfenadine) but can also bebeneficial (Ritonavir), the ingestion of grapefruits & GFJ
  • Cytochrome P450s in Disease: Cancer & Hypoxia
  • Estrogens as circulating hormones
  • Highlight Aromatase metabolic activities
  • Explain the major catalytic cycle of Aromatase
  • Explain therapeutic need for Aromatase inhibitors
  • Discuss structural features of Aromatase
  • Approved aromatase drugs and the DDIs of Anastrozole
  • When to switch from TAM to Aromatase Inhibitors
  • Discuss risk factors in breast cancer & breast cancer prevention